1. Technical Field
The present invention relates to 4-oxybenzopyran derivatives having a prolongation effect on the functional refractory period, which are used for treatments of arrhythmia in mammal including human beings.
2. Background Art
As benzopyran derivatives, there have been known 4-acylaminobenzopyran derivatives exemplified by Cromakalim (Japanese Patent Application Laid-Open No. Sho 58-67683). These 4-acylaminobenzopyran derivatives exemplified by Cromakalim are known to open an ATP sensitive K+channel and to be effective for the treatment of hypertension or asthma, but there has not been any mention as to the treatment for arrhythmia based on the prolongation effect on the functional refractory period.
Now, conventional antiarrhythmic agents having the prolongation effect on the functional refractory period as a main function (such as Class I drugs of antiarrhythmic agent classification according to Vaughan Williams, or d-sotalol belonging to Class III) having highly dangerous arrhythmic inducing actions that can result in sudden death such as torsades de pointes based on extension of ventricular muscle action potential relating to the prolongation effect on the functional refractory period, which become the therapeutic problems. Thus, agents having less side effects are desired.
The inventors of the present invention have made an intensive study of compounds having the prolongation effect on the functional refractory period more selective for atrium muscle than for ventricular muscle, and found that the compound of the general formula (I) has a prolongation effect on the functional refractory period selective for atrium muscle without any influence on the refractory period of ventricular muscle and action potential parameters.
The inventors of the present invention have studied eagerly 4-oxybenzopyran derivatives, and found that the compound of the formula (I) has the strong prolongation effect on the functional refractory period, and it is useful as an antiarrhythmic agent. The present invention has been made based on this finding.
The present invention relates to a 4-oxybenzopyran derivative of the formula (I) 
wherein, R1 and R2 represent each independently a hydrogen atom; a C1-6 alkyl group in which said alkyl group may be optionally substituted with a halogen atom, a C1-6 alkoxy group or a hydroxyl group; or a phenyl group in which said phenyl group may be optionally substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkyl group or a C1-6 alkoxy group;
R3 represents a hydroxyl group or a C1-6 alkylcarbonyloxy group;
R4 represents a hydrogen atom, a C3-6 cycloalkyl group, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkylaminocarbonyl group or a di-C1-6 alkylaminocarbonyl group in which said C1-6 alkyl group, said C1-6 alkylcarbonyl groups, said C1-6 alkylaminocarbonyl group and said di-C1-6 alkylaminocarbonyl group may be each optionally substituted with a halogen atom, a C1-6 alkoxy group, a C1-6 alkoxy group substituted by a halogen atom; a carboxyl group, a C1-6 alkoxycarbonyl group, a hydroxyl group, or an aryl group or a heteroaryl group; in which said aryl group and said heteroaryl group may be optionally substituted with (R9)4, in which R9 represents a halogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkyl group substituted by a halogen atom or a C1-6 alkoxy group; a C1-6 alkoxy group, A C1-6 alkoxy group substituted by a halogen atom; or R9 represents a nitro group, a cyano group, a formyl group, a formamide group, an amino group, a C1-6 alkylamino group, a di-C1-6 alkylamino group, a C1-6 alkylcarbonylamino group, a C1-6 alkylsulfonylamino group, an aminocarbonyl group, a C1-6 alkylaminocarbonyl group, a di-C1-6 alkylaminocarbonyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminosulfonyl group, a C1-6 alkylsulfonyl group, a carboxyl group or an arylcarbonyl group if r represents 2 r 3; or R4 represents an aryl group or a heteroaryl group in which said aryl group and said heteroaryl group may be optionally substituted with (R10)q in which R10 has the same meaning as R9, q represents an integer of 1-3, and each R10 may be same or different if q represents 2 or 3;
n represents an integer of 0-4;
X represents xe2x80x94C(xe2x95x90O)NR7xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94NHC(xe2x95x90O)NHxe2x80x94 or xe2x80x94S(O)2NHxe2x80x94 (in which R7 and R8 represent each independently a hydrogen atom or a C1-6 alkyl group);
R5 represents a hydrogen atom; or a group of the formula: 
in which R12 represents a hydrogen atom; a halogen atom; a C1-6 alkyl group in which the alkyl group may be optionally substituted with a halogen atom or a C1-6 alkoxy group; a C1-6 alkoxy group in which said alkoxy group may be optionally substituted with a halogen atom; a phenyl group in which said phenyl group may be optionally substituted with a halogen atom, a hydroxyl group, a C1-6 alkyl group or a C1-6 alkoxy group; or R12 represents a hydroxyl group, a nitro group, a cyano group, a formyl group, a formamide group, an amino group, a C1-6 alkylamino group, a di-C1-6 alkylamino group, a C1-6 alkylcarbonylamino group, a C1-6 alkylsulfonylamino group, an aminocarbonyl group, a C1-6 alkylaminocarbonyl group, a di-C1-6 alkylaminocarbonyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminosulfonyl group, a C1-6 alkylsulfonyl group, a carboxyl group or an arylcarbonyl group, m represents an integer of 1-3, and each R12 may be same or different if m represents 2 or 3, and R13 represents a hydrogen atom or a C1-6 alkyl group; and
R6 represents a hydrogen atom, a halogen atom, a nitro group or a cyano group;
or a pharmaceutically acceptable salt thereof.
The compound according to the present invention has the strong prolongation effect on the functional refractory period and it can be used as a drug for treating arrhythmia.
Respective substituents for the compound (I) according to the present invention are illustrated specifically as follows.
Herein, xe2x80x9cnxe2x80x9d means normal, xe2x80x9cixe2x80x9d means iso, xe2x80x9csxe2x80x9d means secondary, xe2x80x9ctxe2x80x9d means tertiary, xe2x80x9ccxe2x80x9d means cyclo, xe2x80x9coxe2x80x9d means ortho, xe2x80x9cmxe2x80x9d means meta, and xe2x80x9cpxe2x80x9d means para.
As C1-6 alkyl groups, there may be mentioned methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, cyanomethyl and hydroxymethyl, etc.
Preferably, there may be mentioned methyl, ethyl, n-propyl, i-propyl and n-butyl.
As halogen atoms, there may be mentioned a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, there may be mentioned a fluorine atom, a chlorine atom and a bromine atom.
As C1-6 alkoxy groups, there may be mentioned methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy, 2,2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy and 3,3-dimethyl-n-butoxy, etc.
Preferably, there may be mentioned methoxy, ethoxy, n-propoxy and i-propoxy.
As C1-6 alkylcarbonyloxy groups, there may be mentioned methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy, s-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-pentylcarbonyloxy, neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 1,1,2-trimethyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxy and 3,3-dimethyl-n-butylcarbonyloxy, etc.
Preferably, there may be mentioned methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy and t-butylcarbonyloxy.
As C3-6 cycloalkyl groups, there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc.
Preferably, there may be mentioned cyclopropyl, cyclobutyl and cyclohexyl.
As C1-6 alkylcarbonyl groups, there may be mentioned methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propyl-carbonyl, n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentyl-carbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl and 3-hexylcarbonyl.
Preferably, there may be mentioned methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl and n-butylcarbonyl.
As C1-6 alkylaminocarbonyl groups, there may be mentioned methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylamino-carbonyl, s-butylaminocarbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-pentylaminocarbonyl, neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl and 3-hexylaminocarbonyl, etc.
Preferably, there may be mentioned methyaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl and n-butylaminocarbonyl.
As di-C1-6 alkylaminocarbonyl groups, there may be mentioned dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl, di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl, di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl and di-3-hexylaminocarbonyl, etc.
Preferably, there may be mentioned dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl and di-n-butylaminocarbonyl.
As C1-6 alkoxycarbonyl groups, there may be mentioned methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxy carbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl and 3-hexyloxycarbonyl, etc.
Preferably, there may be mentioned methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl.
As aryl groups, there may be mentioned phenyl, biphenyl, naphthyl, anthryl and phenanthryl etc.
Preferably, there may be mentioned phenyl, biphenyl and naphthyl.
As heteroaryl groups, there may be mentioned 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl, 5-isobenzothienyl, 2-chromenyl, 3-chromenyl, 4-chromenyl, 5-chromenyl, 6-chromenyl, 7-chromenyl, 8-chromenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purinyl, 2-purinyl, 3-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-pterdinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl and 3-furazanyl, etc.
Preferably, there may be mentioned 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.
As C1-6 alkylamino groups, there may be mentioned methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-penylamino, 2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino, t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino, c-hexylamino, 1-methyl-n-pentylamino, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamino, etc.
Preferably, there may be mentioned methylamino, ethylamino, n-propylamino, i-propylamino and n-butylamino.
As di-C1-6 alkylamino groups, there may be mentioned dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-c-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, di-c-butylamino, di-1-pentylamino, di-2-pentylamino, di-3-pentylamino, di-i-pentylamino, di-neopentylamino, di-t-pentylamino, di-c-pentylamino, di-1-hexylamino, di-2-hexylamino, di-3-hexylamino, di-c-hexylamino, di-(1-methyl-n-pentyl)amino, di-(1,1,2-trimethyl-n-propyl)amino, di-(1,2,2-trimethyl-n-propyl)amino, di-(3,3-dimethyl-n-butyl)amino, methyl(ethyl)amino, methyl(n-propyl)amino, methyl(i-propyl)amino, methyl (c-propyl)amino, methyl(n-butyl)amino, methyl(i-butyl)amino, methyl(s-butyl)amino, methyl(t-butyl)amino, methyl(c-butyl)amino, ethyl(n-propyl)amino, ethyl(i-propyl)amino, ethyl(c-propyl)amino, ethyl(n-butyl)amino, ethyl(i-butyl)amino, ethyl(s-butyl)amino, ethyl(t-butyl)amino, ethyl(c-butyl amino, n-propyl(i-propyl)amino, n-propyl(c-propyl)amino, n-propyl(n-butyl)amino, n-propyl(i-butyl)amino, n-propyl(s-butyl)amino, n-propyl(t-butyl)amino, n-propyl(c-butyl)amino, i-propyl(c-propyl)amino, i-propyl(n-butyl)amino, i-propyl(i-butyl)amino, i-propyl(s-butyl)amino, i-propyl(t-butyl)amino, i-propyl(c-butyl)amino, c-propyl(n-butyl)amino, c-propyl(i-butyl)amino, c-propyl(s-butyl)amino, c-propyl(t-butyl)amino, c-propyl(c-butyl)amino, n-butyl(i-butyl)amino, n-butyl(s-butyl)amino, n-butyl(t-butyl)amino, n-butyl(c-butyl)amino, i-butyl(s-butyl)amino, i-butyl(t-butyl)amino, i-butyl(c-butyl)amino, s-butyl(t-butyl)amino, s-butyl(c-butyl)amino and t-butyl(c-butyl)amino, etc.
Preferably, there may be mentioned dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino and di-n-butylamino.
As C1-6 alkylcarbonylamino groups, there may be mentioned methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, 1-pentyl-carbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino, neopentylcarbonylamino, t-pentyl-carbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino and 3-hexylcarbonylamino, etc.
Preferably, there may be mentioned methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino and n-butylcarbonylamino.
As C1-6 alkylsulfonylamino groups, there may be mentioned methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, n-butylsulfonylamino, i-butylsolfonylamino, s-butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, i-pentylsulfonylamino, neopentylsulfonylamino, t-pentyl sulfonylamino, 1-hexylsulfonylamino, 2-hexylsulfonylamino and 3-hexylsulfonylamino, etc.
Preferably, there may be mentioned methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino and n-butylsulfonylamino.
As C1-6 alkylsulfonyl groups, there may be mentioned methanesulfonyl and ethanesulfonyl.
As arylcarbonyl groups, there may be mentioned benzoyl, p-methylbenzoyl, p-t-butylbenzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and p-cyanobenzoyl.
Preferably, there may be mentioned benzoyl, p-nitrobenzoyl and p-cyanobenzoyl.
As preferable compounds used in the present invention, the following compounds may be mentioned.
(1) A 4-oxybenzopyran derivative of the formula (I) or pharmaceutically acceptable salt thereof, wherein R1 and R2 represent both methyl groups and R3 represents a hydroxyl group.
(2) A 4-oxybenzopyran derivative or pharmaceutically acceptable salt according to the aforementioned (1), wherein R6 represents a hydrogen atom or a nitro group.
(3) A 4-oxybenzopyran derivative or pharmaceutically acceptable salt thereof according to the aforementioned (2), wherein X represents xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NMexe2x80x94, xe2x80x94S(O)2NHxe2x80x94 or xe2x80x94NHC(xe2x95x90O)NHxe2x80x94.
(4) A 4-oxybenzopyran derivative or pharmaceutically acceptable salt thereof according to the aforementioned (3), wherein X represents xe2x80x94C(xe2x95x90O)NHxe2x80x94 and R5 represents 
(5) A 4-oxybenzopyran derivative or pharmaceutically acceptable salt thereof according to the aforementioned (4), wherein R4 represents a C1-6 alkyl group.
Specific examples of the compounds that can be used in the present invention are shown as follows, but the present invention is not limited thereto. Herein, xe2x80x9cMexe2x80x9d means a methyl group, xe2x80x9cEtxe2x80x9d means an ethyl group, xe2x80x9cPrxe2x80x9d means a propyl group, xe2x80x9cBuxe2x80x9d means a butyl group, xe2x80x9cPenxe2x80x9d means a pentyl group, xe2x80x9cHexxe2x80x9d means a hexyl group, xe2x80x9cPhxe2x80x9d means a phenyl group, xe2x80x9cAcxe2x80x9d means an acetyl group (COCH3), and xe2x80x9cxe2x88x92xe2x80x9d means a bond, respectively.
The compound according to the present invention has asymmetric carbon atoms at 3-position and 4-positon, thus optical isomers thereof based on the asymmetric carbon atoms are present, which can be used in the application of the present invention similar to racemate thereof. Further, a cis or trans isomer based on configuration at 3-position and 4-position may be included, but the trans isomer is preferable.
Further, when the compounds can form their salts, the pharmaceutically acceptable salts can be also used as active ingredients.
As pharmaceutically acceptable salts, there may be mentioned hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, benzoates, tartrates, phosphates, lactates, maleates, fumarates, malates, gluconates and salicylates, etc.
Preferably, there may be mentioned hydrochlorides and methanesulfonates.
Then, the preparation method of the compound according to the present invention is illustrated.
Of the compounds of the general formula (I), those wherein R3 represents a hydroxyl group, which are the compounds of formula (I-a), can be obtained by reacting a compound of the general formula (2) with a compound (3) in an inert solvent, as shown in the following reaction scheme.
The compound of the general formula (2) can be synthesized according to known methods (methods described in J. M. Evans et al., J. Med. Chem. 1984, 27, 1127, J. Med. Chem. 1986, 29, 2194, J. T. North et al., J. Org. Chem. 1995, 60, 3397, as well as Japanese Patent Application Laid-Open No. Sho 56-57785, Japanese Patent Application Laid-Open No. Sho 56-57786, Japanese Patent Application Laid-Open No. Sho 58-188880, Japanese Patent Application Laid-Open No. Hei 2-141, Japanese Patent Application Laid-Open No. Hei 10-87650 and Japanese Patent Application Laid-Open No. Hei 11-209366, etc.). 
In this scheme, R1 ,R2 ,R4 ,R5 ,R6 ,x and n are as defined above.
As the solvents used in the reaction of the compound of the general formula (2) with the compound (3), the following may be mentioned.
There may be mentioned sulfoxide type solvents exemplified by dimethylsulfoxide; amide type solvents exemplified by dimethylformamide or dimethylacetamide; either type solvents exemplified by ethyl ether, dimethoxyethane or tetrahydrofuran; halogen type solvents exemplified by dichloromethane, chloroform and dichloroethane; nitrile type solvents exemplified by acetonitrile and propionitrile; aromatic hydrocarbon type solvents exemplified by benzene and toluene; hydrocarbon type solvents exemplified by hexane and heptane; and ester type solvents exemplified by ethyl acetate. Further, the reaction can be carried out in the absence of a solvent. Preferably, ether type solvents and nitrile type solvents may be mentioned.
The reaction temperature is generally from xe2x88x9280xc2x0 C. to the reflux temperature of the reaction solvent, preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.
The molar ratio of the reaction materials is within the range of 0.5-20.0, preferably 1.0-10.0, for the compound (3)/the compound (2).
An acid catalyst may be used in the reaction.
As the acid catalysts used, there may be mentioned inorganic acids exemplified by hydrochloric acid and sulfuric acid, as well as Lewis acids exemplified by aluminum chloride, titanium tetrachloride, boron trifluoride diethyl ether complex, perchloric acid, lithium perchlorate and ytterbium trifluoromethanesulfonate, etc.
Preferably, there may be mentioned sulfuric acid and perchloric acid.
Of the compounds of the general formula (I), those other than the compounds of formula (I-a) described above (those of the formula (I) wherein R3 represents a C1-6 alkylcarbonyloxy group) can be prepared by the preparation methods similar to those described in Japanese Patent Application Laid-Open No. Sho 52-91866 and Japanese Patent Application Laid-Open No. Hei 10-87650, etc.
Syntheses of optically active compounds included in the compounds of the general formula (I) can be attained by utilizing optical resolution methods (Japanese Patent Application Laid-Open No. Hei 3-141286, U.S. Pat. No. 5,097,037 and European Patent No. 409165). Further, syntheses of optically active compounds of the general formula (2) can be attained by utilizing asymmetrical synthetic methods (Japanese National Publication No. Hei 5-507645, Japanese Patent Application Laid-Open No. Hei 5-301878, Japanese Patent Application Laid-Open No. Hei 7-285983, European Patent Application Laid-open No. 535377, and U.S. Pat. No. 5,420,314).
As described above, we, inventors, found that the compound of the general formula (I) has the strong prolongation effect on the functional refractory period. The prolongation effect on the functional refractory period is one of the functions of antiarrhythmic action and an important indicator that can be extrapolated to efficiency for clinical arrhythmia. Conventional antiarrhythmic agents having the prolongation effect on the functional refractory period as the main function (such as d-sotalol belonging to Class III of the antiarrhythmic agent classification according to Vaughan Williams) have quite dangerous arrhythmic inducing actions that can result in sudden death such as torsades de pointes based on extension of ventricular muscle action potential relating to the prolongation effect on the functional refractory period, which become the therapeutic problems for arrhythmia based on atrium (such as supraventricular tachycardia, atrial flutter and atrial fibrillation). In order to solve the problems, we, inventors, carried out searching and studying of compounds having the prolongation effect on the functional refractory period more selective for atrium muscle than for ventricular muscle, and found that the compound of the general formula (I) has the prolongation effect on the functional refractory period selective for atrium muscle without any influence on the functional refractory period of ventricular muscle and action potential parameters. The difference between the present invention by the inventors and the known techniques is to provide the prolongation effect on the functional refractory period selective for atrium muscle by the compound, which is shown by the following facts; without any influence on the action potential sustaining period of removed ventricular muscle and without any influence on the electrocardiogram QT of anesthetized animal. From the above, the compounds of the present invention have no arrhythmic inducing action in ventricular muscle, thus they can provide possibilities of more safe uses for arrhythmia based on atrium muscle than known techniques. The technique according to the present invention is useful for therapeutic or preventive uses as anti-atrial fibrillation agents, anti-atrial flutter agents and anti-atrial tachycardia agents relating to paroxysmal, chronic, preoperative, intraoperative of postoperative atrial arrhythmia, prevention of proceeding to embolus based on atrial arrhythmia, prevention of proceeding to ventricular arrhythmia or tachycardia originated from atrial arrhythmia or tachycardia, and prevention of the life prognosis worsening based on the preventive action for atrial arrhythmia or tachycardia which can be proceeded to ventricular arrhythmia or tachycardia.
The present invention provides a pharmaceutical composition or veterinary pharmaceutical composition containing the compound of the generally formula (I) in an effective amount for these treatments.
As administering forms of the compound according to the present invention, there may be mentioned parenteral administrations by means of injections (subcutaneous, intravenous, intramuscular and intraperitoneal injections), ointments, suppositories and aerosol, or oral administration by means of tablets, capsules, granules, pills, syrups, solutions, emulsions and suspensions, etc.
The above-mentioned pharmaceutical or veterinary pharmaceutical composition contains the compound according to the present invention in an amount of about 0.01-99.5%, preferably about 0.1-30%, of the total composition weight.
In addition to the compound according to the present invention or the composition containing the compound, other pharmaceutically or veterinary pharmaceutically active compounds may be contained.
Further, these compositions may contain the plurality of compounds according to the present invention.
A clinical administration amount varies depending on age, weight and sensitivity of the patient, extent of condition of the patient, etc. and an effective administration amount is generally about 0.003-1.5 g, preferably 0.01-0.6 g, per day for adult. If necessary, however, the amount outside of the above-mentioned range may be used.
The compound according to the present invention is formulated for administration by conventional pharmaceutical means.
That is, tablets, capsules, granules and pills for oral administration are prepared by using excipients such as sucrose, lactose, glucose, starch and mannitol; binders such as hydrozypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methyl cellulose and polyvinyl pyrrolidone; disintegrators such as starch, carboxymethyl cellulose or its calcium salt, crystal cellulose powder and polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, and silica; lubricaing agents such as sodium laurate and glycerol, etc.
Injections, solution, emulsions, suspension, syrups and aerosols are prepared by using solvent for the active ingerdients such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol; surfactants such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil and lecithin; suspending agents such as carboxymethyl sodium salt, cellulose derivatives such as methyl cellulose, tragacanth, and natural rubbers such as gum arabic; and preserves such as p-hydroxybenzoic acid esters, benzalkonium chloride and sorbic acid salts, etc.
For ointments that are transdermally adsorptive pharmaceutics, white vaseline, liquid paraffin, higher alcohols, Macrogol ointments, hydrophilic ointments and aqueous gel-type bases are, for example, used.
Suppositories are prepared by using, for example, cocoa fats, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil and Polysorbate etc.